Project Abstract High risk human papilloma virus related oropharynx carcinoma (HPVOPC) incidence is rapidly increasing, and has surpassed the incidence of cervical carcinoma in the US. Published data show the independent association of post treatment HPV DNA detection in plasma and salivary rinses with HPVOPC recurrence, and concepts in development for NCI supported head and neck clinical trials in HPVOPC currently include research laboratory based assays for detection of HPV DNA in body fluids, including plasma and saliva. This project includes a 1) a UH2 phase for rational development of an HPV DNA based body fluid test based on whole genome sequencing data, followed by analytic validation of this test in plasma and salivary rinses within a CLIA-certified laboratory setting; and, 2) a UH3 clinical validation phase of this test within a CLIA-certified laboratory setting for a cohort of HPVOPC patients. At the conclusion of this project, a rationally designed, optimized test for the presence of HPV DNA in HPV OPC patients w ill be available for clinical trials within a CLIA-certified laboratory setting.